Prenatal dexamethasone exposure disrupts offspring hippocampal neurogenesis and triggers depression-like behaviors via epigenetic regulation

Prenatal glucocorticoid therapy is commonly used to manage preterm fetal delivery risks; however, such exposure elevates the risk of adult psychiatric disorders, though the underlying mechanisms remain elusive. The present study utilized a mouse model exposed to dexamethasone (DEX, a synthetic glucocorticoid) during late pregnancy (GD14.5-GD20.5). Here, we found that prenatal DEX exposure decreased hippocampal expression of Tet1, Yy1, and Ezh2, increased Pten expression, reduced neurogenesis, and induced depression-like behaviors. Mechanistically, prenatal DEX exposure suppressed Tet1 levels in offspring, inhibiting Tet1 enrichment and 5hmC levels in the Yy1 and Ezh2 promoter regions, thereby downregulating their expression. Subsequently, reduced Yy1 and Ezh2 levels disinhibited Pten expression, leading to Pten upregulation that inhibits the PI3K-Akt-mTOR pathway. This cascade ultimately impaired neurogenesis and promoted depression-like behaviors. Notably, administering the Pten inhibitor bpV(pic) or supplementing Tet1 expression to DEX-exposed offspring restored neurogenesis and behavioral phenotypes. In summary, this study demonstrates that prenatal DEX exposure mediates the upregulation of hippocampal Pten expression through epigenetic mechanisms, leading to suppressed neurogenesis and the emergence of depression-like phenotypes. These results elucidate novel signaling mechanisms and contribute to the theoretical framework for understanding how prenatal DEX exposure influences offspring psychiatric health.